Synthesis and Antitumor Activity of 2,4,6-Trisubstituted Novel Quinazoline Derivatives Containing Trifluoromethyl

doi:10.6023/cjoc202107026

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (1): 249-256.DOI: 10.6023/cjoc202107026 Previous Articles Next Articles

Special Issue: 有机氟化学虚拟合辑

ARTICLES

含三氟甲基的2,4,6-三取代喹唑啉衍生物的合成及抗肿瘤活性研究

汪正捷^a^,^b, 戴洪林^a^,^b, 司晓杰^a^,^b, 高潮^a^,^b, 刘丽敏^a^,^b, 张路野^a^,^b, 张洋^a^,^b, 宋亚丹^a^,^b, 赵培荣^a^,^b^,^c, 郑甲信^a^,^b, 可钰^a^,^b^,^*(), 刘宏民^a^,^b^,^c^,^d^,^*(), 张秋荣^a^,^b^,^d^,^*()

a 郑州大学药学院郑州 450001
b 郑州大学新药研究与安全评价协同创新中心郑州 450001
c 郑州大学食管癌防治国家重点实验室郑州 450052
d 郑州大学教育部药物制备关键技术重点实验室郑州 450001

收稿日期:2021-07-12 修回日期:2021-08-13 发布日期:2021-08-28
通讯作者: 可钰, 刘宏民, 张秋荣
基金资助:
国家自然科学基金(U1904163); 国家蛋白质研究项目(2018YFE0195100); 省部共建食管癌防治国家重点实验室资助的开放基金(K2020000X)

Synthesis and Antitumor Activity of 2,4,6-Trisubstituted Novel Quinazoline Derivatives Containing Trifluoromethyl

Zhengjie Wang^a^,^b, Honglin Dai^a^,^b, Xiaojie Si^a^,^b, Chao Gao^a^,^b, Limin Liu^a^,^b, Luye Zhang^a^,^b, Yang Zhang^a^,^b, Yadan Song^a^,^b, Peirong Zhao^a^,^b^,^c, Jiaxin Zheng^a^,^b, Yu Ke^a^,^b(), Hongmin Liu^a^,^b^,^c^,^d(), Qiurong Zhang^a^,^b^,^d()

a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001
b Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001
c State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450052
d Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001

Received:2021-07-12 Revised:2021-08-13 Published:2021-08-28
Contact: Yu Ke, Hongmin Liu, Qiurong Zhang
Supported by:
National Natural Science Foundation of China(U1904163); National Key Research Program of Proteins(2018YFE0195100); Opening Fund from State Key Laboratory of Esophageal Cancer Prevention & Treatment(K2020000X)

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Abstract

In order to find efficient and low toxicity antitumor drugs, a series of novel 2,4,6-trisubstituted quinazoline derivatives containing trifluoromethyl were synthesized and evaluated for their antitumor activities against human cancer cell lines (PC-3, MCF-7, Eca-109, MGC-803, HGC-27, A549, H1975) by using methyl thiazolyl tetrazolium (MTT) assay. Most of compounds exerted moderate to excellent antitumor activity against seven human cancer cells. Among them, N-(3-bromophenyl)-6-methoxy-2-((4-(trifluoromethyl)benzyl)thio)quinazolin-4-amine (16l) showed the best antitumor activity against PC-3 cancer cell line, with the IC₅₀ values of (2.22±0.15) μmol/L, which was better than the positive control of gefitinib. At the same time, and compound 16l could dose-dependently and time-dependently induce PC-3 cells apoptosis.

Key words: trifluoromethyl, quinazoline, synthesis, antitumor activity

Cite this article

Zhengjie Wang, Honglin Dai, Xiaojie Si, Chao Gao, Limin Liu, Luye Zhang, Yang Zhang, Yadan Song, Peirong Zhao, Jiaxin Zheng, Yu Ke, Hongmin Liu, Qiurong Zhang. Synthesis and Antitumor Activity of 2,4,6-Trisubstituted Novel Quinazoline Derivatives Containing Trifluoromethyl[J]. Chinese Journal of Organic Chemistry, 2022, 42(1): 249-256.

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References 27

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Compound	R	IC₅₀/(μmol•L^–1)
Compound	R	PC-3	MCF-7	Eca-109	MGC-803	HGC-27	A549	H1975
16a	H	24.66±0.80	21.32±0.52	25.35±1.28	22.12±1.10	28.51±1.26	29.48±0.77	24.92±1.60
16b	2-F	17.13±0.65	27.03±1.25	24.53±1.62	15.89±0.82	16.40±1.21	26.83±1.17	26.80±1.32
16c	2-Cl	22.27±1.12	>50	>50	32.80±1.65	>50	>50	24.41±1.21
16d	2-Br	16.50±0.53	22.03±0.87	>50	17.07±0.86	35.75±1.55	16.49±0.56	>50
16e	2-CF₃	45.19±1.24	44.22±1.23	43.69±1.55	35.94±1.26	25.07±1.39	45.51±1.19	44.17±1.62
16f	2-CH₃	15.90±1.08	26.23±0.95	32.10±1.85	21.09±1.02	19.00±1.27	39.83±1.61	37.14±1.66
16g	2-OCH₃	36.99±1.63	>50	>50	30.67±1.75	20.09±1.41	28.51±0.45	23.24±0.76
16h	2-OC₂H₅	9.67±0.68	43.55±1.87	47.17±1.81	40.33±1.12	21.47±1.33	29.13±0.65	31.20±1.81
16i	3-Cl-4-F	9.08±0.52	18.90±0.48	13.38±0.32	15.13±0.60	8.26±0.91	18.34±0.60	25.94±0.97
16j	3-Cl	9.38±0.55	18.29±0.68	17.16±0.68	20.66±1.31	18.35±1.26	27.17±0.49	25.20±0.77
16k	3,4-diCl	7.77±0.46	16.00±0.76	9.41±0.22	10.36±1.01	23.86±0.83	26.09±0.85	9.41±0.22
16l	3-Br	2.22±0.15	7.62±0.77	6.21±0.66	4.07±0.79	7.55±0.87	5.93±0.25	8.45±0.41
16m	3-CF₃	3.11±0.15	13.29±0.40	16.30±0.19	5.60±0.29	6.06±0.78	14.71±0.86	21.13±0.81
16n	3-CH₃	7.06±0.67	23.34±0.62	26.65±0.85	14.44±0.75	9.59±1.24	17.22±0.21	24.78±1.69
16o	3-OCH₃	8.81±0.59	26.55±1.64	22.64±1.41	10.84±1.03	22.54±1.33	30.05±1.21	22.64±1.41
16p	3-CN	6.24±0.42	>50	29.23±1.83	3.59±0.55	20.36±0.90	28.12±1.02	29.23±1.83
16q	3-NO₂	3.25±0.51	6.62±0.81	10.00±1.00	6.99±0.84	22.69±0.96	26.60±1.07	10.00±1.00
16r	4-F	7.02±0.58	20.01±0.94	10.28±0.35	19.44±1.28	17.39±0.55	25.28±0.95	10.28±0.35
16s	4-Cl	7.22±0.66	15.06±0.66	15.88±0.56	8.23±0.91	25.75±0.80	21.15±1.35	15.88±0.56
16t	4-Br	9.10±0.40	17.50±0.52	10.55±0.47	17.66±1.24	28.38±0.88	28.95±1.20	10.55±0.47
16u	4-CF₃	3.14±0.41	14.39±0.69	10.82±0.96	11.37±1.05	15.05±0.50	14.75±0.85	10.82±0.96
16v	4-CH₃	13.42±0.47	21.50±1.36	19.04±0.83	25.47±1.87	26.91±1.40	29.77±1.81	19.04±0.83
16w	4-OCH₃	6.55±0.75	28.78±1.29	28.87±0.80	9.51±0.97	30.10±1.26	18.31±0.46	28.87±0.80
Gefitinib^b	—	8.92±0.41	8.15±0.28	10.90±0.81	8.19±0.67	7.91±0.22	6.26±0.83	9.20±0.76

Compound	R	IC₅₀/(μmol•L^–1)
Compound	R	PC-3	MCF-7	Eca-109	MGC-803	HGC-27	A549	H1975
16a	H	24.66±0.80	21.32±0.52	25.35±1.28	22.12±1.10	28.51±1.26	29.48±0.77	24.92±1.60
16b	2-F	17.13±0.65	27.03±1.25	24.53±1.62	15.89±0.82	16.40±1.21	26.83±1.17	26.80±1.32
16c	2-Cl	22.27±1.12	>50	>50	32.80±1.65	>50	>50	24.41±1.21
16d	2-Br	16.50±0.53	22.03±0.87	>50	17.07±0.86	35.75±1.55	16.49±0.56	>50
16e	2-CF₃	45.19±1.24	44.22±1.23	43.69±1.55	35.94±1.26	25.07±1.39	45.51±1.19	44.17±1.62
16f	2-CH₃	15.90±1.08	26.23±0.95	32.10±1.85	21.09±1.02	19.00±1.27	39.83±1.61	37.14±1.66
16g	2-OCH₃	36.99±1.63	>50	>50	30.67±1.75	20.09±1.41	28.51±0.45	23.24±0.76
16h	2-OC₂H₅	9.67±0.68	43.55±1.87	47.17±1.81	40.33±1.12	21.47±1.33	29.13±0.65	31.20±1.81
16i	3-Cl-4-F	9.08±0.52	18.90±0.48	13.38±0.32	15.13±0.60	8.26±0.91	18.34±0.60	25.94±0.97
16j	3-Cl	9.38±0.55	18.29±0.68	17.16±0.68	20.66±1.31	18.35±1.26	27.17±0.49	25.20±0.77
16k	3,4-diCl	7.77±0.46	16.00±0.76	9.41±0.22	10.36±1.01	23.86±0.83	26.09±0.85	9.41±0.22
16l	3-Br	2.22±0.15	7.62±0.77	6.21±0.66	4.07±0.79	7.55±0.87	5.93±0.25	8.45±0.41
16m	3-CF₃	3.11±0.15	13.29±0.40	16.30±0.19	5.60±0.29	6.06±0.78	14.71±0.86	21.13±0.81
16n	3-CH₃	7.06±0.67	23.34±0.62	26.65±0.85	14.44±0.75	9.59±1.24	17.22±0.21	24.78±1.69
16o	3-OCH₃	8.81±0.59	26.55±1.64	22.64±1.41	10.84±1.03	22.54±1.33	30.05±1.21	22.64±1.41
16p	3-CN	6.24±0.42	>50	29.23±1.83	3.59±0.55	20.36±0.90	28.12±1.02	29.23±1.83
16q	3-NO₂	3.25±0.51	6.62±0.81	10.00±1.00	6.99±0.84	22.69±0.96	26.60±1.07	10.00±1.00
16r	4-F	7.02±0.58	20.01±0.94	10.28±0.35	19.44±1.28	17.39±0.55	25.28±0.95	10.28±0.35
16s	4-Cl	7.22±0.66	15.06±0.66	15.88±0.56	8.23±0.91	25.75±0.80	21.15±1.35	15.88±0.56
16t	4-Br	9.10±0.40	17.50±0.52	10.55±0.47	17.66±1.24	28.38±0.88	28.95±1.20	10.55±0.47
16u	4-CF₃	3.14±0.41	14.39±0.69	10.82±0.96	11.37±1.05	15.05±0.50	14.75±0.85	10.82±0.96
16v	4-CH₃	13.42±0.47	21.50±1.36	19.04±0.83	25.47±1.87	26.91±1.40	29.77±1.81	19.04±0.83
16w	4-OCH₃	6.55±0.75	28.78±1.29	28.87±0.80	9.51±0.97	30.10±1.26	18.31±0.46	28.87±0.80
Gefitinib^b	—	8.92±0.41	8.15±0.28	10.90±0.81	8.19±0.67	7.91±0.22	6.26±0.83	9.20±0.76

含三氟甲基的2,4,6-三取代喹唑啉衍生物的合成及抗肿瘤活性研究

Synthesis and Antitumor Activity of 2,4,6-Trisubstituted Novel Quinazoline Derivatives Containing Trifluoromethyl

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